Bis (tetrahydroisoquinolyl) alkanes



United States Patent 3,138,600 BIS(TETRAHYDROISOQUINOLYDALKANES Otis E. Fancher and Shin Hayao, Elkhart, llnd., assignors to Miles Laboratories, Inc., Elkhart, Ind, a corporation of Indiana N0 Drawing. Filed May 25, 1959, Ser. No. 815,295 1 Claim. (Cl. 260-286) This invention relates to new compositions of matter and to a process for their preparation. Particularly, the invention relates to bis(tetrahydroisoquinolyl) alkanes and halogen salts having amebicidal and trypanocidal activity.

The novel compositions of this invention conform to the following general formula:

In the formula above, R represents alkyl groups having from 2 to 6 carbon atoms, R and R represent hydrogen or alkyl groups having from 1 to 4 carbon atoms, R and R represent alkoxy groups having from 1 to 4 carbon atoms or alkylenedioxy groups having from 1 to 3 carbon atoms, and n represents an integer of from 4 to 10, inclusive.

While the values for the substituent radicals given above are operable values, in the preferred compositions of this invention R stands for alkyl groups containing from 2 to 5 carbon atoms, R and R stand for hydrogen or methyl groups, R and R stand for methoxy or methylenedioxy groups.

In addition, the class of bis(tetrahydroisoquinolyl)alkanes of the above formula is limited to those compounds Whose a,w-disubstituted alkylene bridge does not contain less than 12, and preferably not less than 14, carbon atoms. Thus, when the R substituent has a lower carbon content, the value of n is correspondingly higher, and vice versa.

The bis(tetrahydroisoquinolyl)alkanes of this invention, as defined above, have been found to be extremely useful as amebicidal and trypanocidal compositions, particularly, in the form of hydrohalide salts. Although the dihydrochlorides of the compounds are preferably used against amoeba or trypanosomes, other salts such as the hydroiodides or hydrobromides may be used.

PROCEDURE The compounds of the invention are prepared by a procedure which comprises the following steps:

1. Preparation of the dicarb0xamide.A mixture of 2 moles of a primary amine and one mole of a dicarboxylic acid are heated in a nitrogen atmosphere at about 190 200 C. for from 140 hours, depending upon the rate of reaction as influenced by the size of the alkyl substituents of the dicarboxylic acid, the reaction rate being slowed by increase in size of the alkyl groups. This reaction product, a dark melt, is the corresponding dicarboxamide.

Instead of the dicarboxylic acid, the corresponding acid chloride may be used. In this instance 1 mole of the primary amine in 20% NaOH is treated with an ether solution of /2 mole of the dicarboxylic acid chloride at 0 C.

3,138,600 Patented June 23, 1964 "ice uum and the residual bis(3,4-dihydroisoquinolyl)alkane is purified by appropriate procedures.

3. Preparation .01 the bis(tetrahydroisoquinolyl)alkane.-The purified bis(dihydroisoquinolyl)alkane is hydrogenated in the presence of a hydrogenation catalyst to give the desired bis(tetrahydroisoquinolyl)alkane, which is isolated and characterized as the appropriate salt.

This compound may be further alkylated by wellknown procedures to give N-alkyl derivatives. For example, the bis(tetrahydroisoquinolyl)alkane prepared as described above may be treated with formaldehyde and formic acid to give the N-methyl derivative.

N-alkyl derivatives may also be obtained by quaternization of the bis(dihydroisoquinolyl)alkane by treatment with the appropriate alkyl halide followed by catalytic hydrogenation.

A large number of compounds representative of the compounds of this invention were prepared following the general procedure steps as detailed above. To more specifically illustrate this procedure, there is set out below a detailed example of the preparation of a compound in accordance with the formula given above wherein R is nbutyl, R is hydrogen, R is methyl, R and R are methoxy, and n is 5.

Example 1. Preparation of the dicarboxamide.A mixture of 10 g. (0.033 mole) of 5,11-pentadecanedicarboxylic acid and 13 g. (0.067 mole) of alphamethylhornoveratrylamine was heated to 190-200 C. for 5 hours and then cooled to room temperature. There resulted a dark brown solid mass. Trituration with ether gave a tan powder which melted at 114l-l5 C. Anal.Calcd. for C H N O N, 4.28. Found: N, 4.21. This compound was N,N- bis(alpha methylhomoveratryl) 5,11 pentadecanedicarboxamide.

When the acid chloride was used, the procedure for the preparation of the dicarboxamide was as follows:

The diacid chloride was prepared from 15 g. (0.05 mole) of 5,1l-pentadecanedicarboxylic acid (solid isomer) and 30 ml. of thionyl chloride refluxed in solution for 3 hours. Excess thionyl chloride was removed in vacuo (water pump) and the remaining syrup dissolved in ml. of ether. It was added to a well-stirred mixture of 16.5 g. (0.1 mole) of homopiperonylamine and 50 ml. of 20% sodium hydroxide solution at 0 during 10 minutes to give an immediate separation of a white solid. It was stirred at room temperature for an hour and the solid was collected by suction, washed with water, ether, and then with water. The product was dried at 50-60 C. in an oven overnight; yield 27.3 g. (89%), M.P. 164 (softening at 156), UV max. 236.5, 390.5 m (log E, 3.92, 3.88).

A sample was recrystallized twice from aqueous methanol to give a white powder of M.P. 163-165 C. (softening at 159.5). Anal.Calcd. for C H N O N, 4.71. Found: N, 4.81.

2. Preparation 0; the bi s(dihydroisoqainolyl)alkane.- The 'N,N'-bis(alpha-methylhomoveratryl)-5,l l-pentadecanedicarboxamide (6.99) was heated under gentle reflux with 30 ml. of POCl for 30 minutes to give a dark red liquid. The excess POCl was removed by distillation under reduced pressure. The remaining dark syrup was treated with ice water to give a gray syrup. The free base was extracted with benzene and the benzene solution extracted with dilute hydrochloric acid. The acid extract was treated with carbon, filtered, cooled, and made alkaline with ammonia to give a colorless oil. This oil was extracted with ether, dried, and treated with dry hydrochloric acid to give a pale yellow syrup.

3. Preparation of the Bis(tetrahydroisoqainolyl)alkane.-This yellow syrup was dissolved in 100 ml. of

methanol and hydrogenerated at 40 lb. pressure using 0.3 g. of platinum oxide as catalyst. The catalyst was filtered off, the methanol solvent evaporated, and the residue was dissolved in water and made alkaline with 4 C. (d.) after two recrystallizations from isopropanol. Anal.Calcd. for C H N O N, 3.33. Found: N, 3.21; UV max. 223, 254, 310, 373, m (log E, 4.52, 4.36, 4.05, 4.16) in methanol.

ammonia to give a white syrup. This syrup was extracted 5 5,11 bis(6,7-met/zylenedixy-1 ,2,3,4-tetrahydr0-1-is0- with ether, dried over magnesium sulfate, and treated quinolyl)-pentadecane dilzydroiodide.-'Ihe dimethiodide with dry hydrogen chloride. The syrupy dihydrochloride (14 g., 0.017 mole) was dissolved in 200 ml. of methanol was dried over P 0 in a vacuum dessicator to give the and hydrogenated with 0.3 g. of Adams catalyst. It desired final product in the form of a fine colorless took up the calculated amount of hydrogen in 20 hours. powder, melting at 95 -100 C. AnaL-Calcd. for The filtrate was evaporated to dryness in vacuo at 100 C H Cl N O N, 4.03. Found: N, 3.84. to give a pale pink solid, yield 13.0 g., M.P. ca. 120 C.

The preparation of the N-methyl derivative by the use with foaming (softening began at 108 C.). It was disof the formaldehyde-formic acid procedure is as follows: solved in hot isopropanol and then evaporated to dryness 3,8-bis(3-methyl-6,7-dimethoxy 1,2,3,4 tetrahydro-lin vacuo at 100 C. to give a pale pink crystalline solid; isoquinolyl)decane dihydrochloride (23 g., 0.037 mole) 15 yield, 11.7 g., M.P. 135140 C. (after drying at 140 C. was dissolved in 250 ml. of hot water, cooled and made in vacuo). AmzI. Calcd. for C H I N O N, 3.31. basic with aqueous potassium carbonate to give a white Found: N, 3.41 UV max. 222.5, 296 III/L (log E, 4.46, gum which was extracted with ether and dried over an- 3.92) in methanol. hydrous magnesium sulfate. The solvent was removed As was stated above, the compounds within the purand the residue was dissolved in 17 g. (0.38 mole) of 20 view of this invention have amebicidal and trypanocidal formic acid (98100%) and then 13.5 ml. (0.168 mole) activity. of 36% formaldehyde was added. The amebicidal activity was tested in accordance with The resulting solution was heated on a steam bath for the procedure prescribed by the National Institutes of seven hours. It was made acidic with 15% hydrochloric Health and involves the determination of the concentraacid and evaporated to dryness in vacuo at 100 C. to tion of the compounds in gamma per milliliter which is give a brown syrup. The purification was repeated twice sufiicient to kill a unit quantity of Endamoeba lzislolytz'ca as follows: which is carried on Locke's Whole Egg Media (WEL).

The syrup was dissolved in water, treated with Norit, The trypanocidal activities of the compounds were demade basic with aqueous sodium carbonate and the resulttermined by the procedure described in an article by ing syrup was extracted with ether. Finally, the ethereal Bradner and Rawson titled An in Vitro Method of Screensolution was added to ether, saturated with dry hydrogen ing Amebicidal Agents Using the Phillips Culture, apchloride to give a syrup which was washed with ether pearing in Science, 113, 674 (1951). This activity is reand taken up in isopropanol. The alcoholic solution ported as the concentration of the compound in gamma was evaporated to dryness in vacuo and the residue was per milliliter required to kill a unit quantity of further dried over P 0 under high vacuum. The hy- T rypanosoma cruzi carried on a medium prescribed by groscopic powder weighed 19.0 g.; M.P. ca. 165. the National Institutes of Health.

Anal.-Calcd. for C H Cl N O N, 4.28. Found: N, In addition, the toxicity of the compounds were deter- 4.09. mined interperitoneally in mice and orally in rats.

As was stated above, quaternization of the dihydroiso- Physical data, toxicity data, and amebicidal and quinoline with an alkyl halide followed by catalytic hydro- 40 trypanocidal activity of 9 compounds which are repregenation also results in N-alkyl derivatives. This resentative of the novel compositions of matter are set out action proceeds as follows: in Table I below. Included in the table are data on three N,N' (homopiperonyl) 5,11 pentadecanedicarboxcompounds (Nos. 10-12) which are different in that R amide (27.3 g., 0.046 mole) was dissolved in 100 ml. of represents hydrogen atoms, i.e., they contain non-sub hot phosphoryl chloride and the clear pale yellow solustituted straight-chain alkylene bridges, and three comtion was refluxed for 2 hours to give a greenish-yellow pounds (Nos. 13-15) which differ from the inventive solution. Excess phosphoryl chloride was removed at a compounds in that the total carbon content of their diwater pump. The remaining syrup was added to ca. substituted alkylene bridge is less than C TABLE I [Physical and Pharmacological Data on Bis(Tetrahydroisoquinolyl)Alkanes] 5.4 R R. R. R. R. 5:25. a250- .255;

(IP (Oral) 440 I1C4H9 H CH3 5 160-180 55.0 2,828 50 47 11, H CH 6 170 77.5 255 2,480 100 100 455 110.110 H H 5 210 91.5 1,445 50 50 461 HC-JHQ H H 4 275-278 12.0 413 024 100 10 514 [104}19 OH; H 5 -140 92.5 1,000 100 505 C H H H 10 0 76.0 1, 655 50 100 502 c 11. H H 10 254-255 25.5 490 3, 040 100 1, 000 455 0 H 11 H 5 265-266 75.0 1,212 1,500 50 50 487 0511 H CH5 5 -170 55.0 145 a, 040 50 100 450 H H H 5 255 52.5 117 1,525 500 500 454 H H CH; 2 270 1,000 1,000 475 H H CH5 5 255 88.2 490 735 1, 000 1, 000 452 C2H5 H H 4 240-243 78.5 203 854 500 1, 000 447 0 115 H CH5 4 170 97.0 120 491 1,000 500 449 0 11 CH5 CH5 4 79.0 50 04 1, 000 500 100 ml. of methanol to give a clear solution which was made basic with cone. ammonium hydroxide. The resulting syrupy free base was taken up in ether and dried over anhydrous magnesium sulfate.

The solvent was removed at a water pump to leave a syrup to which was added 50 ml. of methyl iodide. The clear yellowish-orange solution was refluxed for an hour to give a deep yellow pasty mixture. Excess methyl iodide was removed in vacuo at 100 C. to give a bright yellow solid mass; yield 35.8 g. (92.5%); M.P. 168170 pounds 10-12) or a total carbon content in excess of of the disubstituted alkylene bridge (Compounds 13-15 which are structural characteristics of the active compounds and dual requisites for amebicidal action. There is thus a nexus between chemical constitution and physiological properties.

In addition, it has been found that the compounds claimed herein also exhibit unexpected and superior amebicidal and/ or trypanocidal properties over certain closely related compounds, disclosed in Osbond et al., Journ. Chem. Soc., pp. 4785-92 (1952). These prior art compounds have a mono (lower)alkyl substitution in the middle of a short alkylene bridge, but as emphasized and demonstrated above, excellent amebicidal activity is imparted to the compounds disclosed herein by a dual requisite of chemical constitution: carbon content of 0 and disubstitution of the alkylene bridge.

More specifically, upon comparison of 1-(6,7-dimethoxy 1,2,3,4 tetrahydro l isoquinolyl) 2 (1,2, 3,4 tetrahydro 6,7 dimethoxy 1 isoquinolylmethyl) butane, a compound of the Osbond reference, and 5,11- bis(6,7 dimethoxy 1,2,3,4 tetrahydro *1 isoquino- 1yl)pentadecane, Compound No. 3 of the table, with emetine hydrochloride as standard of comparison, which is active within 48 hours at 1:100,000 to 1:400,000 dilution, it was found, in duplicate in vitro tests, that the Osbond compound did not fall within the emetine range of activity, while Compound No. 3 fell within the amebicidal range of emetine. By present criteria the Osbond compound can therefore not be considered as amebicidal.

These comparative results establish that the compounds, claimed herein, possess unexpected and superior antimicrobial properties over the structurally closest prior art compounds.

To summarize briefly, this invention relates to novel compositions of matter which have outstanding and unexpected amebicidal and trypanocidal activity. The compounds may be generally described as bis(tetrahydroisowherein R is an alkyl group of from 2 to 6, preferably 2 to 5 carbon atoms; wherein R and R are selected from the group consisting of hydrogen atoms and alkyl groups of from 1 to 4 carbon atoms, preferably methyl groups; wherein R and R are selected from the group consisting of alkoxy groups of from 1 to 4 carbon atoms, preferably methoxy groups, and alkylenedioxy groups of from 1 to 3 carbon atoms, preferably methylenedioxy groups; wherein n is an integer from 4 to 10; and wherein the total carbon content of the a,w-disubstituted alkylene bridge is not less than C This application'is a continuation-in-part to our application, Serial No. 670,888, filed July 10, 1957, now abandoned.

What is claimed is:

5,11 bis(6,7 methylenedioxy 1,2,3,4 tetrahydrol-isoquinolyl)-pentadecane dihydrochloride.

References Cited in the file of this patent Fancher et al., J. Amer. Chem. Soc., vol. 80, pp. 14516 (1958). 

